Regulation of the functions of the retinal pigment epithelium (RPE) may involve receptors and G proteins that are expressed preferentially in RPE cells. Our past efforts to identify novel G proteins in RPE cells have been successful. We have also investigated G protein signaling mechanisms in RPE cells by molecular cloning of RPE-specific cDNAs that may encode the components of signal transduction pathways. Our recent findings point to the presence of a unique receptor-mediated G protein-coupled process in the RPE cell. We have identified in bovine RPE cells a novel G protein-coupled receptor, tentatively referred to as RPE-retinal G protein-coupled receptor or RGR. This novel heptahelical receptor is notably homologous, to the subfamily of visual pigments, and it has been shown by in situ hybridization to be selectively expressed in RPE cells, cells in the inner nuclear layer, and specific cells of the ganglion cell layer. It is not expressed in the photoreceptors, or in tissues other than the retina, except possibly the brain. The localization of this receptor in the RPE, the high level of expression of its mRNA, and its homology to the visual pigments suggest that the function of this receptor is important in the visual process involving the RPE. The RGR gene may encode a novel opsin homologue that binds retinaldehyde. Its function may be to catalyze retinaldehyde isomerization or act as a trapping protein for 11-cis-retinal. An alternative function of RGR may be to mediate a novel G protein response pathway by binding to an activating ligand and coupling to a heterotrimeric G protein. We predict that the RGR gene is highly conserved in vertebrates. The abundance of RGR in the RPE cell would strongly suggest that it participates in a major and specialized role of the RPE. We will test these and other hypotheses by biochemical characterization of the RGR gene product. The objectives of this proposal are to further characterize the RGR gene, determine the putative receptor function of RGR, and elucidate specialized G protein pathways and regulation in RPE cells. The molecular cloning of this selectively expressed opsin or retinochrome homologue provides an entry point for further investigation of RPE function, differentiation, and disease.